The year 1982 marked the beginning of a new era in the diagnosis and treatment of male sexual impotence. At that time, the new development was the use of papavetine as a drug which, when injected intracavernously, was capable of inducing a penile erection in humans, Virag, R. "Intracavernous injection of papaverine for erectile failure". Lancet 2: 938 (1982).
Regrettably, universal medical experience with this drug over several years revealed the severity of some of its side-effects, Junemann, K. P. and Alken, P. "Pharmacotherapy of erectile dysfunction; a review". Int. J. Impotence Res. 1, 71-93 (1988). A major disadvantage of papaverine was the occurrence of unduly prolonged erection with the danger of priapism. Papaverine was also tried in combination with the alpha sympathetic blocker phentolamine, Zorgniotti, A. W. and Lefleur, R. S. J. Urol., 133(1): 39-41, (1985). Phenoxybenzamine, another alpha-adrenergic blocker was also tested, Brindley, G. S. Br. J, Psychiatry, 143: 332-337 (1983). The use of phenoxybenzamine for the management of impotence was abandoned at this time because of evidence obtained from experiments with animals suggesting that this drug could have carcinogenic activity. JARC. Phenoxybenzamine and phenoxybenzamine hydrochloride. JARC Monogr. Eval. Carcinog. Risk Chem. Hum., 24: 185-194, 1980; Hoffman, B. B., Lefkowitz, R. J. Adrenergic receptor antagonist. Goodman and Gilman's. The Pharmacological Basis of Therapeutics, eighth edition New York: Pergamon Press, c1990. p. 225.
Experiments with Cynomolgus monkeys showed that after 1 to 2 weekly intracavernous injections (of papaverine) led, after a period of 12 months, to extensive fibrosis in the distal areas of the erectile organ. In humans, this reaction could have very negative long term consequences: fibrotic corpora cavernosa become incapable of erection, Abozeid, M. et al. J. Urol., 138(5): 1263-1266 (1987).
In 1986, Ishii et al injected for the first time prostaglandin E.sub.1 into human corpora cavernosa for the treatment of organic impotence, Ishii, N. et al. "Therapeutic trial with prostaglandin E.sub.1 for organic impotence". Jap. J. Imp., 1: 54-962 (1986). See also Ishii, N. et al "Intracavernous injection of prostaglandin E.sub.1 for the treatment of erectile impotence". J. Urol., 141(2): 323-325 (1989). Since it is a drug of natural occurrence in the body and could be expected to cause fewer side-effects than papaverine, PGE.sub.1 became rapidly and universally accepted, Junemann, K. P. and Alken, P. Int. J. Imp. Res., 1: 71-93 (1988).
The use of a triple combination of PGE.sub.1, papaverine and phentolamine was introduced in 1991, Bennett et al. J. Urol., 146(6): 1564-1565 (1991). However, prolonged erections have been reported following the use of such a combination, von-Heyden et al. J. Urol., 149(5 Pt 2): 1288-1290 (1993). The use of prostaglandin E.sub.1 is often rejected by patients because of the painfulness of its injection. Waldhauser, M. et al., J. Urol., 140(3): 525-527 (1988).
In spite of initially promising evidences of a possible role of nitric oxide (NO) in the mechanics of normal human penile erection, Rajfer, J. et al., N. Eng. J. Med., 326: 90-94 (1992) in 1992 Porst, (Porst, H., Int. J. Impotence Res., 4(Suppl. 2): A91 (1992)) compared the erectogenic efficiency of 1 mg of SIN-1 (Linsindomin-Corvasal.RTM.) against 20 .mu.g of PGE1 (Prostavasin.RTM.), both of them administered by intracavernous vias to 40 consecutive patient complaining of erectile failure. According to the latter author: ". . . SIN-1 is considerably less effective than PGE1 and will therefore, not play a major role in the management of male impotence".
Virag, in 1982, was the first to demonstrate the erectogenic effect of a vasoactive drug injected directly into the patient's epigastric artery. The type of therapy in which the patients conduct their own treatment via intracavernous administration of drugs is called self-injection therapy. Virag. R. et al. Angiology, 35: 79-87 (1984). See also U.S. Pat. Nos. 4, 127,118; 4,766,889 and 4,857,059, incorporated by herein reference, in their entirety.
Alternative agents, like acetylcholine (which causes marked systemic effects but only short-lasting erections), as well as a number of orally acting vasoactive substances such as yohimbine, Terbutalin, betanechol, levodopa, Verapamil or theophylline have not been successful for the treatment of male erectile dysfunction.
There is a clear need for the development of new drugs capable of acting by injection or topical administration, as facilitators, potentiators and inducers of full penile erection in man, and have reduced or diminished side effects over the current methods of therapy for the diagnostic and therapeutic treatment of various erectile dysfunction's in men.